N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3

被引：74

作者：

Angell, Richard M.

Atkinson, Francis L.

Brown, Murray J.

Chuang, Tsu Tshen

Christopher, John A.

Cichy-Knight, Maria

Dunn, Allison K.

Hightower, Kendra E.

Malkakorpi, Susanna

Musgrave, James R.

Neu, Margarete

Rowland, Paul

Shea, Robyn L.

Smith, Jeffery L.

Somers, Donald O.

Thomas, Sonia A.

Thompson, Gladstone

Wang, Ruolan

机构：

[1] GlaxoSmithKline R&D, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline R&D, Harlow CM19 5AW, Essex, England

[3] GlaxoSmithKline Inc, Collegeville, PA 19426 USA

[4] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 05期

关键词：

kinase; inhibitor; JNK; JNK3; MAPK; selective;

D O I：

10.1016/j.bmcl.2006.12.003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC(50) 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC(50) 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38 alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：1296 / 1301

页数：6

共 27 条

[1] SCALES OF SOLUTE HYDROGEN-BONDING - THEIR CONSTRUCTION AND APPLICATION TO PHYSICOCHEMICAL AND BIOCHEMICAL PROCESSES [J].

ABRAHAM, MH .

CHEMICAL SOCIETY REVIEWS, 1993, 22 (02) :73-83

[2]

ADAMS JL, 2004, PROTEIN CRYSTALLOGRA, pCH2

[3] Hydrogen-bond acceptor and donor properties of divalent sulfur (Y-S-Z and R-S-H) [J].

Allen, FH ;

Bird, CM ;

Rowland, RS ;

Raithby, PR .

ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1997, 53 :696-701

[4]

BARKER MD, Patent No. 05073232

[5] SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase [J].

Bennett, BL ;

Sasaki, DT ;

Murray, BW ;

O'Leary, EC ;

Sakata, ST ;

Xu, WM ;

Leisten, JC ;

Motiwala, A ;

Pierce, S ;

Satoh, Y ;

Bhagwat, SS ;

Manning, AM ;

Anderson, DW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (24) :13681-13686

[6] IsoStar: A library of information about nonbonded interactions [J].

Bruno, IJ ;

Cole, JC ;

Lommerse, JPM ;

Rowland, RS ;

Taylor, R ;

Verdonk, ML .

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1997, 11 (06) :525-537

[7] A small molecule-kinase interaction map for clinical kinase inhibitors [J].

Fabian, MA ;

Biggs, WH ;

Treiber, DK ;

Atteridge, CE ;

Azimioara, MD ;

Benedetti, MG ;

Carter, TA ;

Ciceri, P ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Galvin, M ;

Gerlach, JL ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Insko, MA ;

Lai, AG ;

Lélias, JM ;

Mehta, SA ;

Milanov, ZV ;

Velasco, AM ;

Wodicka, LM ;

Patel, HK ;

Zarrinkar, PP ;

Lockhart, DJ .

NATURE BIOTECHNOLOGY, 2005, 23 (03) :329-336

[8] HETEROCYCLEN AUS CH-ACIDEN NITRILEN .7. 2-AMINO-THIOPHENE AUS ALPHA-OXO-MERCAPTANEN UND METHYLENAKTIVEN NITRILEN [J].

GEWALD, K .

CHEMISCHE BERICHTE-RECUEIL, 1965, 98 (11) :3571-&

[9] p38 MAPK signalling cascades in inflammatory disease [J].

Herlaar, E ;

Brown, Z .

MOLECULAR MEDICINE TODAY, 1999, 5 (10) :439-447

[10] Physiological regulation of the β-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiation [J].

Kimberly, WT ;

Zheng, JB ;

Town, T ;

Flavell, RA ;

Selkoe, DJ .

JOURNAL OF NEUROSCIENCE, 2005, 25 (23) :5533-5543

← 1 2 3 →